tbuckley/cabot-search huggingface dataset:
PB1829: ARGENTINEAN REAL WORLD EXPERIENCE ON MIDOSTAURIN PLUS INTENSIVE CHEMOTHERAPY VS INTENSIVE CHEMOTHERAPY TO TREAT FLT3 POSITIVE ACUTE MYELOID LEUKEMIA PATIENTS
Authors: A. Navickas, J. González, M. M. Rivas, M. Clavijo, N. Carnelutto, M. E. Funes, M. J. Mela Osorio, R. Mariano, M. L. Rapan, M. Moirano, I. Rey, S. Cranco, J. E. Giunta, R. Ramirez, M. B. Castro, A. Enrico, A. Gimenez Conca, C. Belli
Journal: HemaSphere (2022)

Background: Midostaurin has been approved by EMA and FDA in combination with intensive chemotherapy (CMT) for FLT3 positive AML based on improved survival. In Argentine was included among therapy strategies in 2018. The real-world experience in day-to-day practice is limited. Aims: To examine the impact of introduction of midostaurin within the backbone to treat FLT3+ AML patients in an Argentinean cohort. Methods: This is a retrospective analysis of 120 FLT3+ AML patients intensively treated with or without midostaurin excluding APL- and CBF-AML, from the Argentine Society database of 1200 AML diagnosed between March-13/Dec-21 including 20 centers. Responses were evaluated according to the ELN 2017 criteria for intensive chemotherapy (CMT). Statistical analysis included Chi2/Fisher’s exact test, Kaplan-Meier survival analysis, censoring or not at HSCT, to last follow-up or death. Results: FLT3 variants were 103 (86%) ITD, 15 (13%) TKD and 2 (1%) ITD/TKD. Seventy-two patients received first line treatment with standard 7 + 3 CMT and 48 added midostaurin. Sex ratio M/F was 0.6 (47/73) with a median age of 50.7 years (15.1-76.4), being 25% >60 years old, 26% an ECOG>1, 17% a Charlson’s Index (CCI)>2, 95 (97%) intermediate MRC karyotypes (23 not available), 43 (43%) NPM1+ (21 not available). No differences were observed between both populations regarding basal characteristics. The median time to treatment initiation was 3 days, and with a median follow-up of 8.2 months, 84 (68%) died with an early mortality at 28 days of 9.6% (1/11 received midostaurin). Regarding responses on those treated with CMT 64% (n=46) obtained Complete Remission (CR), subsequently 37 pts (51%) received consolidation with high doses of CMT, 13 pts relapsed, and 26 received HSCT. Within the MDT cohort, 79% (n=38) achieved CR, 37 (77%) were consolidated, 7 pts relapsed, and 25 received HSCT. The inclusion of MDT to CMT improved the outcome of our patients. The overall survival censoring at HSCT was 7.0 vs 4.7 (95%CI 1.7-12.4 vs 3.1-6.4, p=0.002), not censoring 12.1 vs 7.7 (95%CI 0.4-23.8 vs 5.5-9.9, p=0.008). Among those who achieved CR, the OS was 24.8 vs 10.3 (95%CI 7.9-41.7 vs 6.7-13.9, p=0.046) and 11.9 vs 6.4 (95%CI 9.5-14.4 vs 5.4-7.4, p=0.015), without differences regarding relapse free survival, evaluated to last follow-up (median not reached, p=0.800). No statistical differences were observed regarding survival after HSCT (9.6 vs 10.3, p=0.773). In our media FLT3 inhibitors are not approved as maintenance therapy after HSCT. Summary/Conclusion: Our results in day-to-day practice confirm that midostaurin associated with CMT improved the outcome of FLT3 positive AML patients.
PB1759: TWENTY-ONE YEARS’ EXPERIENCE OF ADOLESCENTS AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH PEDIATRIC PROTOCOL: MONOCENTRIC STUDY
Authors: I. Frikha, N. Siala, I. Turki, M. Mdhaffar, I. Ben Amor, N. Louati, Y. Fakhfakh, F. Kallel, O. Kassar, M. Charfi, S. Hadijji, H. Mnif, M. Elloumi
Journal: HemaSphere (2022)

Background: Several retrospective studies have confirmed that adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric protocols have better outcomes than similarly aged patients treated with adult protocols. Aims: We reported results and feasibility of a pediatric-based protocol (EORTC 58951) in adolescents and young adults. Methods: From January 2000 to December 2020, 95 patients aged 16 to 30 years with newly diagnosed ALL were treated, in the department of hematology department of Hedi Chaker Hospital, according to the EORTC 58951 pediatric protocol. Further leukemia characteristics (Sex, White Blood cell count, Blasts phenotype, Cytogenetic results), we studied the protocol results: response to prophase), risk group stratification (average: AR1 and AR2, very high: VHR), complete remission rate (CR), death rate, relapse rate and 5 years survivals (overall OS and event free EFS). Results: Ninety-five AYA ALL were treated with the pediatric protocol. Medium age was 20 years (range: 16 to 30 years). The patients were 60 males and 35 females (SR=1.71). A WBC> 100 G/l was noted in 28%. A T blast phenotype was noted in 48% of cases. Cytogenetic abnormalities were noted in 40% of cases. Fourteen patients (14%) were treated according AR1 arm, 50 patients (53%) according AR2 arm and 31 patients (33%) according VHR arm. CR rate was 81% after one course and 89% after 2 courses. Induction death was noted in 7% and post-induction death was noted in 14%. Twenty-eight patients from VHR group with familial donor underwent allograft. Thirty-one patients treated with VHR arm protocol were eligible for allogenic stem-cell transplantation (SCT), among them 21 patients had a familial donor and 15 patients were allograft (48%). Relapse was observed in 25 patients (26%) among them 4 after allograft. Fifty-four of relapses occurred within a year of CR. The median follow up was 129 months. The five years OS and EFS were respectively 49% and 47%. Summary/Conclusion: The results of this pediatric based study show that response to therapy and prognostic in adolescent and young adults were better than those treated with adult protocols and tolerability of chemotherapy is acceptable. However, OS and EFS, better than adult ALL treated by adult protocol (OS= 14%, EFS=14% in previous local study) but less than describe in the literature.
P1743: IDENTIFYING DUTCH HOSPITALIZED PATIENTS AT HEMATOLOGY WARDS WITH A LIMITED LIFE EXPECTANCY: A SUBGROUP ANALYSIS OF A FLASH MOB STUDY
Authors: A. van der Velden, A. de Heij, C. Hazenberg, A. Reyners, P. de Graeff
Journal: HemaSphere (2022)

Background: Disease trajectories and perspectives differ considerably between various subtypes of hematological malignancies, whereas determination of the transition point from a curative to palliative approach to care can be challenging. It is not known how many in hospital patients with hematological diseases have a decreased life expectancy and if these patients receive palliative care. Aims: This study aimed to investigate how many inpatients with a probable limited life expectancy were hospitalized in Dutch hospitals on a given day, if a palliative care team (PCT) was involved or involvement was considered desirable. Methods: A flash mob study was conducted in Dutch hospitals on the 16th of April 2021 at all wards, except the pediatric and obstetric wards, emergency and day care departments. For all hospitalized patients, nurses and doctors independently answered the surprise question (SQ): "Would you be surprised if this patient died within the next 12 months?", estimated life expectancy of less than three months and involvement of the palliative care team (PCT). In addition, categorized baseline characteristics and treatment limitations were registered. In this study we report a subgroup analysis for hematology wards in university medical centers. Results: All eight academic hospitals in the Netherlands participated in the flash mob study. Surveys were completed for 2178 patients, of which 210 patients were admitted to hematology wards. The SQ was negatively answered in 40% of cases by doctors and 36% by nurses, respectively. Agreement for the SQ between doctors and nurses was moderate (kappa 0.41). In comparison, the life expectancy of inpatients was estimated to be less than 12 months in approximately 49% at medical oncology wards and approximately 37% at internal medicine wards according to the doctors in academic centers. Life expectancy was estimated to be less than three months in 8.6% and 7.1% of patients by doctors and nurses, respectively (kappa 0.58) for in hospital patients at hematology wards. Treatment limitations were recorded in 17.1% of all patients, and in 25% of patients with an estimated life expectancy of less than 12 months. The PCT was involved in 1.6% of cases, and involvement was desirable in 3.3% according to doctors, increasing to 11.1% and 4.2% when life expectancy was estimated to be less than three months. Summary/Conclusion: In more than one-third of patients admitted to hematology wards, the SQ was answered negatively, suggesting a limited life expectancy and possible palliative care needs. PCT involvement was considered of added value by healthcare professionals in 4.9% of all admitted patients at hematology wards. Further studies should focus on exploration of palliative care needs of hospitalized patients and possible benefits of timely implementation of specialized palliative care.
Evolution of miRNA-Binding Sites and Regulatory Networks in Cichlids
Authors: Tarang K Mehta, Luca Penso-Dolfin, Will Nash, Sushmita Roy, Federica Di-Palma, Wilfried Haerty
Journal: Molecular Biology and Evolution (2022)

The divergence of regulatory regions and gene regulatory network (GRN) rewiring is a key driver of cichlid phenotypic diversity. However, the contribution of miRNA-binding site turnover has yet to be linked to GRN evolution across cichlids. Here, we extend our previous studies by analyzing the selective constraints driving evolution of miRNA and transcription factor (TF)-binding sites of target genes, to infer instances of cichlid GRN rewiring associated with regulatory binding site turnover. Comparative analyses identified increased species-specific networks that are functionally associated to traits of cichlid phenotypic diversity. The evolutionary rewiring is associated with differential models of miRNA- and TF-binding site turnover, driven by a high proportion of fast-evolving polymorphic sites in adaptive trait genes compared with subsets of random genes. Positive selection acting upon discrete mutations in these regulatory regions is likely to be an important mechanism in rewiring GRNs in rapidly radiating cichlids. Regulatory variants of functionally associated miRNA- and TF-binding sites of visual opsin genes differentially segregate according to phylogeny and ecology of Lake Malawi species, identifying both rewired, for example, clade-specific and conserved network motifs of adaptive trait associated GRNs. Our approach revealed several novel candidate regulators, regulatory regions, and three-node motifs across cichlid genomes with previously reported associations to known adaptive evolutionary traits.
PB1749: APOPTOTIC EFFECT OF FLUMATINIB COMBINED WITH BCL2 INHIBITOR ON PH+ B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Y. Gu, C. Song, Z. Ge
Journal: HemaSphere (2022)

Background: Philadelphia chromosome (Ph+) is the most common genetic abnormality of B-cell acute lymphoblastic leukemia (B-ALL), and also an independent prognostic high-risk marker. In addition to allogeneic hematopoietic stem cell transplantation, now tyrosine kinase inhibitor (TKI) has greatly improved the prognosis of patients with Ph+ B-cell ALL. Flumatinib is a kind of TKI originally developed in China and has been approved for chronic myeloid leukemia (CML). ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in B-ALL. However, there is no report about the anti-tumor effect of flumatinib in combination with Bcl-2 inhibitor in B-ALL. Aims: We explore the effect of flumatinib combined with Bcl-2 inhibitor on cell proliferation arrest and apoptosis in SUP-B15 human Ph+ B-cell ALL cells. Methods: CCK-8 assay was used to analyze the proliferation of SUP-B15 cells treated with flumatinib only, ABT-199 only, combination group, and vehicle control. All groups were treated for 48h at the same time. Apoptosis assay was performed with Annexin V staining following flow cytometry analysis. Expression of the apoptosis-associated gene and protein level was detected by real-time PCR and western blot, respectively. Results: Flumatinib and ABT-199 were sensitive to SUP-B15 in both single or combined treatment in a dose-dependent manner (Fig. 1A). The IC50 of flumatinib was 2.4uM, and ABT-199 5.5nM in the cells treated for 48 hours. Combination of various doses of flumatinib with 5.5nM (IC50) ABT-199 showed significantly higher proliferation arrest than that of either single drug, and CalcuSyn analysis showed a synergistic effect of the two drugs on the cell proliferation arrest (Fig. 1B). The combination of flumatinib with ABT-199 also significantly increased the apoptosis rate of SUP-B15 (39.2±1.2%) compared to either flumatinib (25.3±0.3%) or ABT-199 (10.6±0.7%) (p<0.05) (Fig. 1C). Furthermore, the combination treatment showed significantly higher expression of apoptosis-related proteins, Bax, Bad, Caspase-3 and Caspase-9 compared to either single drug in mRNA level by qPCR (p<0.05) (Fig. 1D) and protein level by western blot (Fig. 1E). Image:Summary/Conclusion: Both single drugs of flumatinib and ABT-199 are sensitive to SUP-B15 human Ph+ B-cell ALL cells. The combination of flumatinib with ABT-199 has a synergistic effect on cell proliferation arrest and apoptosis of the cells, revealing the potential of the novel combination for therapy of Ph+ B-cell ALL.
P722: IS THE SECOND-GENERATION TYROSINE KINASE INHIBITOR A BETTER THERAPY THAN IMATINIB FOR PERSONS WITH CHRONIC MYELOID LEUKEMIA PRESENTING IN ACCELERATED-PHASE?
Authors: X. Zhang, S. Yang, Y. Liu, Q. Jiang
Journal: HemaSphere (2022)

Background: Although most patients with chronic myeloid leukemia (CML) were presenting in the chronic phase at diagnosis, approximately 5% presented with features of accelerated phase. The features of accelerated phase were variably defined by different criteria, such as MD Anderson and European LeukemiaNet (ELN) criteria most often used. Regardless of these criteria used to defined accelerated phase, only scant data were available regarding the prognostic co-variates for outcome. Moreover, evidence that patients could benefit more from the second generation (2G-) tyrosine kinase inhibitor (TKI) than imatinib as initial therapy was still extremely limited. Aims: Explore whether patients with chronic myeloid leukemia (CML) presenting in accelerated-phase could benefit from initial second-generation tyrosine kinase inhibitor (2G-TKI) therapy. Methods: We interrogated data from consecutive patients with CML presenting in accelerated phase at diagnosis by the MD Anderson criteria (n = 325) or ELN criteria (n = 275). Propensity score matching (PSM) analysis was used to compare cytogenetic and molecular responses and outcomes in those receiving initial imatinib versus a 2G-TKI. COX multi-variable regression model was performed to identify the prognostic co-variates. Results: In the cohort defined by MD Anderson criteria, PSM analysis showed that patients receiving initial 2G-TKI (n = 89) had higher probability of achieving a CCyR (p = 0.01), MMR (p = 0.04) and MR4.5 (p = 0.004) than those receiving imatinib (n = 156), however, probabilities of FFS, PFS and survival were similar. Multi-variable analyses showed that lower platelets and higher blasts in blood or bone marrow were significantly-associated with poor FFS, PFS and/or survival (Figure A). In an attempt to determine whether choice of therapy contributed to the differences in responses and outcomes, platelets < 600 × 10E+9/L and blood / bone marrow blasts ≥ 5% were identified as the prognostic categorical co-variates by ROC analyses. The entire cohort were classified into low- (possessing none of these co-variates, n = 57), intermediate (possessing any 1 of these co-variates, n = 127) or high-risk (possessing all of these co-variates, n = 61) subgroups. There were significant differences in probabilities of outcomes among these risk subgroups (all p values < 0.001, Figure B). In each risk subgroup, patients receiving initial 2G-TKI had the similar outcomes to those receiving imatinib except higher incidences of responses including CCyR, MMR and MR4.5. The same results were observed in the cohort defined by ELN criteria. Image:Summary/Conclusion: Initial 2G-TKI lead to similar outcomes as imatinib in patients with CML presenting in accelerated-phase except higher therapy responses.
PB2136: PLANNED-USE GLUCARPIDASE FOR OUTPATIENT HIGH DOSE METHOTREXATE (HD-MTX) ADMINISTRATION IN PATIENTS WITH CNS LYMPHOMA (CNSL) DURING THE COVID-19 PANDEMIC
Authors: L. Schaff, M. Lobbous, D. Carlow, L. DeAngelis, L. B. Nabors, C. Grommes
Journal: HemaSphere (2022)

Background: First-line treatment for central nervous system lymphoma (CNSL) consists of high-dose methotrexate (HD-MTX) combination therapy, a potentially curative strategy. Administration of HD-MTX typically requires inpatient hospital admission for monitoring and aggressive hydration to prevent toxicity. During the height of the COVID-19 pandemic, patients were reluctant to present for this potentially curative chemotherapy out of concern for increased risk of COVID exposure during hospital admission. Aims: This study explores the feasibility of planned-use glucarpidase, a recombinant bacterial enzyme that rapidly reduces serum MTX levels, to facilitate the outpatient administration of HD-MTX for patients with CNSL. Methods: Eligible adult patients had lymphoma isolated to the CNS, normal renal function, and had previously tolerated standard inpatient HD-MTX. After informed consent was obtained, MTX 3.5 g/m2 was administered in the outpatient setting along with intravenous hydration. Patients returned 24 hours after MTX administration for glucarpidase 2000u and additional hydration. MTX level was determined by high pressure liquid chromatography (HPLC) 48 hours following start of administration. Results: Twenty outpatient treatments of HD-MTX with glucarpidase were administered to a total of 7 patients (men=3, women=4). Patients had a median age of 71 (range, 47-73) and baseline Karnofsky Performance Status of 90 (range 70-90). They received either one (n=1), two (n=3), three (n=2), or seven (n=1) treatments on study. MTX levels were reduced to <100 nmol/L at 48 hours following 20/20 treatments (100%). Adverse events at least possibly attributed to glucarpidase included grade 1 and 2 fatigue (n=3). Events possibly attributed to MTX included grade 1 and 2 fatigue (n=2), nausea (n=2), and vomiting (n=1). Five treatments were associated with an elevated creatinine, one of which was grade 2 and resolved to baseline following additional hydration. There was one grade 3 decreased lymphocyte count attributed to MTX. Remaining lab abnormalities were grade 1 or 2, also attributed to MTX, and included elevated alanine aminotransferase (n=3), elevated aspartate aminotransferase (n=3), anemia (n=1), hypocalcemia (n=1), hypokalemia (n=3), and decreased lymphocyte count (n=4). Out of an abundance of caution, all patients received leucovorin prior to documentation of MTX clearance. None of the patients required hospital admission during treatment. Anti-glucarpidase antibody data from enrolled patients is being analyzed. Summary/Conclusion: This study demonstrates feasibility of outpatient HD-MTX administration with planned-use glucarpidase for a select patient population during the COVID-19 pandemic. We are currently enrolling to a larger study of planned-use glucarpidase for repeated doses of outpatient HD-MTX (NCT03684980).
Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5–17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial
Authors: Aaron M Samuels, Daniel Ansong, Simon K Kariuki, Samuel Adjei, Anne Bollaerts, Christian Ockenhouse, Nelli Westercamp, Cynthia K Lee, Lode Schuerman, Dennis K Bii, Lawrence Osei-Tutu, Martina Oneko, Marc Lievens, Maame Anima Attobrah Sarfo, Cecilia Atieno, Danielle Morelle, Ashura Bakari, Tony Sang, Erik Jongert, Maame Fremah Kotoh-Mortty, Kephas Otieno, François Roman, Patrick Boakye Yiadom Buabeng, Yaw Ntiamoah, Opokua Ofori-Anyinam, Tsiri Agbenyega, David Sambian, Albert Agordo Dornudo, Lydia Nana Badu, Kwame Akoi, Evans Antwi, Kelvin Onoka, Kevin K'Orimba, Paul Ndaya Oloo, Elizabeth Leakey, Emilia Gvozdenovic, Cristina Cravcenco, Pascale Vandoolaeghe, Johan Vekemans, Karen Ivinson
Journal: The Lancet Infectious Diseases (2022)
Correction: A novel approach for relapsed/refractory FLT3mut+acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib
Authors: Ke-xin Li, Hui-yang Wu, Wan-ying Pan, Meng-qi Guo, De-zhi Qiu, Yan-jie He, Yu-hua Li, Dong-Hua Yang, Yu-xian Huang
Journal: Molecular Cancer (2022)
PB2278: INVESTIGATION ON THE STATUS OF INFECTION IN PATIENTS WITH MULTIPLE MYELOMA
Authors: D. Lan, L. Shi, L. Gao
Journal: HemaSphere (2022)

Background: multiple myeloma; infection; clinical features; predisposing factors Aims: To preliminarily explore the clinical features, distribution of infection sites and susceptibility factors of infection in patients with multiple myeloma. Methods: he clinical data of 505 patients with multiple myeloma who were treated in our hospital from January 2015 to October 2021 were retrospectively analyzed, and they were divided into infection group and control group according to whether infection occurred. The baseline data, clinical characteristics, infection site, and blood biochemical indexes during infection were collected and analyzed. Results: Among the 505 patients, 109 patients had infection, and the infection rate was about 21.6%. Lung was the main infection site in 53 cases, followed by 6 cases of urinary system infection, 3 cases of skin infection, 2 cases of perianal infection, and 45 cases with no clear infection foci. In the distribution of pathogenic bacteria, a total of 13 gram-negative bacteria, 9 gram-positive bacteria, 13 fungi and 1 virus were detected. Males and patients with education below high school were more susceptible to infection (P<0.05). Summary/Conclusion: The incidence of infection in patients with multiple myeloma is about 21.6%. The lung is the main infection site, and gram-negative bacteria are the main infection bacteria. Male and low education are the susceptibility factors for infection.
Intra-articular botulinum toxin A injection for painful base-of-thumb osteoarthritis: a double-blind, randomised, controlled, phase 3 trial (RHIBOT)
Authors: Christelle Nguyen, Hendy Abdoul, Raphaël Campagna, Henri Guerini, Léa Jilet, Catherine Bedin, Franck Chagny, Gaëlle Couraud, Camille Daste, Jean-Luc Drapé, Rémy Fléchon, Charlotte Gil, Corinne Guérin, Marie-Martine Lefèvre-Colau, Serge Poiraudeau, Estelle Randriamampandry, Alexandra Roren, Antoine Feydy, François Rannou
Journal: The Lancet Rheumatology (2022)